Local Renin-angiotensin System Research Articles

Regulatory Effect of Vitamin D on Renin Expression at Maternal-Fetal Interface

To investigate the regulatory effect and mechanism of vitamin D on the local renin-angiotensin system at maternal-fetal interface in the pathological process of preeclampsia (PE). The mRNA and protein expression of renin in decidua of normal pregnancy and PE placentas was determined by RT-PCR and Western blot. Normal decidual tissues were treated with active and inactive vitamin D for 48 h in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Normal decidual stromal cells and glandular epithelial cells were isolated and purified, and identified by immunocytochemical staining. RT-PCR was used to examine the mRNA of vdr, cyp27 b1, cyp24 a1, and renin in the two types of cells and in decidual tissue, and the mRNA products were subjected to gel electrophoresis. These two cell types were treated with active and inactive vitamin D in vitro and the expressions of renin and vitamin D deactivating enzyme CYP24A1 were determined by RT-PCR and Western blot. Decidual gland epithelial cells were treated with protein kinase A (PKA) activator forskolin or inhibitor H89 to explore the interaction between PKA pathway and vitamin D in the regulation of renin expression. The expression of renin in PE decidua was significantly higher than that of normal control at transcriptional and translational levels ( P<0.05). Vitamin D treatment could significantly down-regulate the expression of renin in normal decidua tissues ( P<0.05), while it significantly up-regulated CYP24A1 expression ( P<0.001). Decidual stromal cells and gland epithelial cells were successfully isolated from decidual tissue. Compared with that in decidual stromal cells, the mRNA level of vitamin D-related molecules in gland epithelial cells was more similar to that in decidual tissue. Active or inactive vitamin D treatment significantly inhibited the expression of renin in glandular epithelial cells ( P<0.05), but the expression of renin in decidual stromal cells was not affected. However, the treatment of active or inactive vitamin D in these two kinds of cells significantly increased the expression of CYP24A1 ( P<0.001). Active vitamin D could significantly inhibit the upregulation of renin by PKA agonist forskolin, and could inhibit the expression of renin through synergy with PKA inhibitor H89. The expression of renin in placental decidua is up-regulated in patients with PE, and the activation of local renin-angiotensin system at the maternal-fetal interface may be involved in the pathogenesis of PE. Vitamin D can specifically down-regulate renin expression in human decidual gland epithelial cells by competing with the PKA pathway. Vitamin D supplementation may have potential value for clinical intervention of PE.

Renal Denervation Influences Angiotensin II Types 1 and 2 Receptors.

The sympathetic and renin-angiotensin systems (RAS) are two critical regulatory systems in the kidney which affect renal hemodynamics and function. These two systems interact with each other so that angiotensin II (Ang II) has the presynaptic effect on the norepinephrine secretion. Another aspect of this interaction is that the sympathetic nervous system affects the function and expression of local RAS receptors, mainly Ang II receptors. Therefore, in many pathological conditions associated with an increased renal sympathetic tone, these receptors' expression changes and renal denervation can normalize these changes and improve the diseases. It seems that the renal sympathectomy can alter Ang II receptors expression and the distribution of RAS receptors in the kidneys, which influence renal functions.

Immune status comparison in patients with atrial fibrillation or flutter on the base of arterial hypertension

Abstract Aims Atrial fibrillation (AF) and atrial flutter (AFl) take the second place between supraventricular arrhythmias and lead to severe complications such as stroke and heart failure. Mostly these arrhythmias occur on the background of arterial hypertension (AH). The inflammatory theory of arrhythmogenesis in AF and AFl has attracted researcher's attention in recent years. The aim of our work is to compare the immune status of patients with paroxysmal and persistent forms of AF and AFl in patients with AH. Material and methods The study involved 103 patients with hypertension and arrhythmias, who were divided into three main groups according to the form of AF/AFl: group 1 (n=35) – with paroxysmal form of AF, group 2 (n=38) - with persistent form of AF, group 3 (n=30) – with persistent form of AFl. For comparison, 2 control groups were formed: 4 (n=23) – patients with hypertension, but without a history of arrhythmias and 5 (n=21) – almost healthy people. The immune status of these patients was assessed by determining the level of monocytes (Mc), lymphocytes subpopulations and T-regulatory cells (T-reg) in the peripheral blood using flow cytometry. Results It was noted that the number of classical CD14++CD16- and intermediate CD14++CD16+ Mc was significantly higher in patients with persistent AF and AFl comparing with patients without arrhythmias and healthy people (p&amp;lt;0.005). This fraction of Mc is able to produce proinflammatory cytokines and activate the local renin-angiotensin system, thus triggering the processes of fibrosis in the myocardium. Amount of non-classical CD14+CD16++ Mc was significantly lower in the second group both quantitatively and in percentage (p&amp;lt;0.005). The count of T cells with natural killer (TNK) activity was higher in all groups comparing to normal value, so statistical significance was observed only in comparison with the fifth group. The highest quantity of T-reg cells was found in healthy people comparing to other groups and a strong mathematical significance was obtained in all cases (p&amp;lt;0.005), both comparing the values in percentage and in μl. Conclusions Patients with AF and AFl on the hypertension background comparing to hypertensive patients without arrhythmias or healthy people have an increased activity of proinflammatory subpopulation of monocytes, higher amount of T-cells with natural killer activity and reduced T-regulatory cells, whose main function is to control the immune response. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): NSC “M.D. Strazhesko Institute of Cardiology” NAMS of Ukraine

Role of the renin-angiotensin system in the development of COVID-19-associated neurological manifestations.

SARS-CoV-2 causes COVID-19, which has claimed millions of lives. This virus can infect various cells and tissues, including the brain, for which numerous neurological symptoms have been reported, ranging from mild and non-life-threatening (e.g., headaches, anosmia, dysgeusia, and disorientation) to severe and life-threatening symptoms (e.g., meningitis, ischemic stroke, and cerebral thrombosis). The cellular receptor for SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), an enzyme that belongs to the renin-angiotensin system (RAS). RAS is an endocrine system that has been classically associated with regulating blood pressure and fluid and electrolyte balance; however, it is also involved in promoting inflammation, proliferation, fibrogenesis, and lipogenesis. Two pathways constitute the RAS with counter-balancing effects, which is the key to its regulation. The first axis (classical) is composed of angiotensin-converting enzyme (ACE), angiotensin (Ang) II, and angiotensin type 1 receptor (AT1R) as the main effector, which -when activated- increases the production of aldosterone and antidiuretic hormone, sympathetic nervous system tone, blood pressure, vasoconstriction, fibrosis, inflammation, and reactive oxygen species (ROS) production. Both systemic and local classical RAS’ within the brain are associated with cognitive impairment, cell death, and inflammation. The second axis (non-classical or alternative) includes ACE2, which converts Ang II to Ang-(1–7), a peptide molecule that activates Mas receptor (MasR) in charge of opposing Ang II/AT1R actions. Thus, the alternative RAS axis enhances cognition, synaptic remodeling, cell survival, cell signal transmission, and antioxidant/anti-inflammatory mechanisms in the brain. In a physiological state, both RAS axes remain balanced. However, some factors can dysregulate systemic and local RAS arms. The binding of SARS-CoV-2 to ACE2 causes the internalization and degradation of this enzyme, reducing its activity, and disrupting the balance of systemic and local RAS, which partially explain the appearance of some of the neurological symptoms associated with COVID-19. Therefore, this review aims to analyze the role of RAS in the development of the neurological effects due to SARS-CoV-2 infection. Moreover, we will discuss the RAS-molecular targets that could be used for therapeutic purposes to treat the short and long-term neurological COVID-19-related sequelae.

(Pro)renin Receptor and Blood Pressure Regulation: A Focus on the Central Nervous System.

The renin-angiotensin system (RAS) is classically described as a hormonal system in which angiotensin II (Ang II) is one of the main active peptides. The action of circulating Ang II on its cognate Ang II type-1 receptor (AT1R) in circumventricular organs has important roles in regulating the autonomic nervous system, blood pressure (BP) and body fluid homeostasis, and has more recently been implicated in cardiovascular metabolism. The presence of a local or tissue RAS in various tissues, including the central nervous system (CNS), is well established. However, because the level of renin, the rate-limiting enzyme in the systemic RAS, is very low in the brain, how endogenous angiotensin peptides are generated in the CNS-the focus of this review-has been the subject of considerable debate. Notable in this context is the identification of the (pro)renin receptor (PRR) as a key component of the brain RAS in the production of Ang II in the CNS. In this review, we highlight cellular and anatomical locations of the PRR in the CNS. We also summarize studies using gain- and loss-of function approaches to elucidate the functional importance of brain PRR-mediated Ang II formation and brain RAS activation, as well as PRR-mediated Ang II-independent signaling pathways, in regulating BP. We further discuss recent developments in PRR involvement in cardiovascular and metabolic diseases and present perspectives for future directions.

Molecular imaging on ACE2-dependent transocular infection of coronavirus.

A transocular infection has been proved as one of the main approaches that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) invades the body, and angiotensin‐converting enzyme 2 (ACE2) plays a key role in this procedure. Dynamic and quantitative details on virus distribution are lacking for virus prevention and drug design. In this study, a radiotraceable pseudovirus packed with an enhanced green fluorescent protein (EGFP) gene, 125I‐CoV, was prepared and inoculated in the unilateral eye of humanized ACE2 (hACE2) mice or ACE2‐knockout (ACE2‐KO) mice. Single‐photon emission computed tomography/computed tomography images were acquired at multiple time points to exhibit ACE2‐dependent procedures from invasion to clearance. Positron emission tomography (PET) and western blot were performed to quantify ACE2 expression and verify the factors affecting transocular infection. For the transocular infection of coronavirus (CoV), the renin–angiotensin–aldosterone system (RAAS), lungs, intestines, and genital glands were the main targeted organs. Due to the specific anchor to ACE2‐expressed host cells, virus concentrations in genital glands, liver, and lungs ranked the top three most and stabilized at 3.75 ± 0.55, 3.30 ± 0.25, and 2.10 ± 0.55% inoculated dose (ID)/mL at 48 h post treatment. Meanwhile, ACE2‐KO mice had already completed the in vivo clearance. In consideration of organ volumes, lungs (14.50 ± 3.75%ID) and liver (10.94 ± 0.71%ID) were the main in‐store reservoirs of CoV. However, the inoculated eye (5.52 ± 1.85%ID for hACE2, 5.24 ± 1.45%ID for ACE2‐KO, p > 0.05) and the adjacent brain exhibited ACE2‐independent virus infection at the end of 72 h observation, and absolute amount of virus played a key role in host cell infection. These observations on CoV infection were further manifested by infection‐driven intracellular EGFP expression. ACE2 PET revealed an infection‐related systematic upregulation of ACE2 expression in the organs involved in RAAS (e.g., brain, lung, heart, liver, and kidney) and the organ that was of own local renin–angiotensin system (e.g., eye). Transocular infection of CoV is ACE2‐dependent and constitutes the cause of disturbed ACE2 expression in the host. The brain, genital glands, and intestines were of the highest unit uptake, potentially accounting for the sequelae. Lungs and liver were of the highest absolute amount, closely related to the respiratory diffusion and in vivo duplication. ACE2 expression was upregulated in the short term after infection with CoV. These visual and quantitative results are helpful to fully understanding the transocular path of SARS‐CoV‐2 and other CoVs.

Modeling of Mechanisms Providing the Overall Control of Human Circulation

Multiple humoral and nervous mechanisms, each influencing the cardiovascular system (CVS) with its specific dynamics and power, had been evolutionarily saved both in animals and in human organisms. Most of such mechanisms are considered to be controllers of CVS’s function, but there is no concept clearly explaining the interaction of global and local controllers in intact human organisms under physiological or pathological conditions. Methodological and ethical constraints create practically insuperable obstacles while experiments on animals mainly concern artificial situations with certain switched-of mechanisms. Currently, mathematical modeling and computer simulations provide the most promising way for expanding and deepening our understanding of regulators’ interactions. As most of CVS’s models describe only partial control mechanisms, a special model (SM) capable of simulating every combination of control mechanisms is encouraged. This paper has three goals: i) to argue the uncial modeling concept and its physiological basis, ii) to describe SM, and iii) to give basic information about SM’s test research. SM describes human hemodynamics, which is under influence of arterial baroreceptor reflexes, peripheral chemoreceptor reflexes, central (CRAS) and local (lRAS) renin-angiotensin systems, local ischemia, and autoregulation of total brain flow. SM, performed in form of special software (SS), is tested under specific endogenous and/or exogenous alterations. The physiologist using SS can easily construct the desirable configuration of regulator mechanisms, their actual state, and scenarios of computer experiments. Tests illustrated the adequateness of SM, are the first step of SM’s research. Nuances of the interaction of modeled regulator mechanisms have to be illustrated in special publications.

Practical Applications of The Unreasonable Attractiveness of More ESG Data

The prorenin receptor is an accessory subunit of the vacuolar H⁺-ATPase, suggesting that it has fundamental functions beyond activation of the local renin-angiotensin system. Podocytes express the prorenin receptor, but its function in these cells is unknown. Here, podocyte-specific, conditional, prorenin receptor-knockout mice died of kidney failure and severe proteinuria within 4 weeks of birth. The podocytes of these mice exhibited foot process effacement with reduced and altered localization of the slit-diaphragm proteins nephrin and podocin. Furthermore, the podocytes contained numerous autophagic vacuoles, confirmed by enhanced accumulation of microtubule-associated protein 1 light chain 3-positive intracellular vesicles. Ablation of the prorenin receptor selectively suppressed expression of the V₀ c-subunit of the vacuolar H⁺-ATPase in podocytes, resulting in deacidification of intracellular vesicles. In conclusion, the prorenin receptor is important for the maintenance of normal podocyte structure and function.

Amelioration of Hypertension by Oryeongsan through Improvements of Body Fluid and Sodium Balance: Roles of the Renin-Angiotensin System and Atrial Natriuretic Peptide System.

Oryeongsan (Wulingsan in China and Goreisan in Japan), a formula composed of five herbal medicines, has long been used for the treatment of imbalance of the body fluid homeostasis in Asian countries. However, the mechanism by which Oryeongsan (ORS) improves the impaired body fluid and salt metabolism is not clearly defined. The present study was performed to define the role of the cardiorenal humoral system in the ORS-induced changes in blood pressure and renal function in hypertension. Experiments were performed in normotensive and two-kidney, one-clip hypertensive rats. Changes in the fluid and salt balance were measured in rats individually housed in metabolic cages. Changes in the systemic and local renin-angiotensin system (RAS) and cardiac natriuretic peptide hormone system (NPS) were evaluated. ORS water extract was administered by oral gavage (100 mg/kg daily) for 3 weeks. ORS induced diuresis and natriuresis along with an increase in glomerular filtration rate and downregulation of the Na+/H+ exchanger 3 (NHE3) and aquaporin 2 expression in the renal cortex and medulla, respectively. Furthermore, treatment with ORS significantly decreased systolic blood pressure with contraction of body sodium and water accumulation in hypertensive rats. ORS-induced changes were accompanied by modulation of the RAS and NPS, downregulation of the systemic RAS and cardiorenal expression of angiotensin-converting enzyme (ACE) and angiotensin II subtype 1 (AT1) receptor, and upregulation of the plasma ANP concentration and cardiorenal expression of ANP, ACE2, Mas receptor, and AT2 receptor. These findings indicate that ORS induces beneficial effects on the high blood pressure through modulation of the RAS and NPS of the cardiorenal system, suppression of the prohypertensive ACE-AT1 receptor pathway and NHE3, accentuation of the antihypertensive ACE2-Mas axis/AT2 receptor pathway in the kidney, suppression of the systemic RAS, and elevation of the plasma ANP levels and its synthesis in the heart. The present study provides a biological basis for the use of ORS in the treatment of impaired volume and pressure homeostasis.

Hematological aspects of the COVID-19 syndrome.

Viral infections could complicate hematopoiesis and, in some cases, they may worsen the clinical prognosis of blood disorders. SARS-CoV-2 and COVID-19, as a viral disease, can have serious impact on the disease course of hematological neoplastic diseases and can cause hematological complications. The aim of this paper is to review the hematologic aspects of COVID-19 syndrome and the potential management options for SARS-CoV-2 including the convalescent plasma, hemostatic agents and proper anticoagulant treatment. Up to February 2022, literature searches were performed using the internet search engines MEDLINE and EMBASE: (i) COVID-19; (ii) Hematology. PRISMA flow diagram described the COVID-19 and hematology search. According to our COVID-19 and hematology research on research databases, we included 82 studies in the current paper. The issues of the impact of the COVID-19 pandemic on hematological diseases, the role of t-lymphocytes in donor lymphocyte infusion and viruses, hemato-immunologic research in COVID-19, local bone marrow renin-angiotensin system and viral infections, clinical management of COVID-19 infection via hemostatic agents, immune plasma treatment of COVID-19, anticoagulant treatment of COVID-19 associated thrombosis are comprehensively described in this paper. The final episode of this pandemic will include the "chimerism-mediated immunotherapy" that will eventually lead to end of the COVID-19 process. The recent Omicron variant seems to have unique evasion effects on the interferon gene expression which will boost the chimerism-mediated immunotherapy without high mortality rates.

Renin-angiotensin system in normal pregnancy and in preeclampsia: A comprehensive review.

The activation of the Renin Angiotensin System (RAS) is required during pregnancy and it seems that RAS dysfunction has some important effects on pathological pregnancy conditions, including preeclampsia (PE). The objective of this review is to summarize and to discuss the role of the RAS in normal pregnancy and in PE. We found evidence that the RAS is important for the evolution of pregnancy under physiological conditions and plays an important role in the pathogenesis of PE. In normal gestation, almost all circulating components of RAS are increased and there is a general state of non-reactivity to the vasoconstrictor actions of Angiotensin (Ang) II. In PE, changes in the circulating levels of RAS components occur, especially with an intense decrease in the levels of Ang I, Ang II and Ang-(1-7). Our findings endorse the idea that PE is a disease whose cornerstone relies on altered placental physiology. There are high tissue levels of Ang II type 1 receptor (AT1R) in the musculature of the blood vessels and in the placenta, generating a state of increased sensitivity to the vasoconstrictor action of Ang II. AT1R autoantibodies (AT1R-AA) might be one of the key points for the vicious cycle of PE, as these molecules are synthesized in situations of hypoxia and enhance placental vasoconstriction, causing even more hypoxia. Further studies are needed to investigate the role of circulating RAS, uteroplacental RAS and local RAS molecules from other tissues related to the pathogenesis of PE.

The pathobiological harmony between the local pulmonary/ bone marrow RAS and its management via tissue-RAS modulating agents in COVID-19

Coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to public health and healthcare systems. It presents unusual pathophysiological effects mainly characterized by immune-inflammatory response and prothrombotic state causing acute respiratory distress syndrome and multiple organ failure. SARS-CoV-2 enters target cells after binding to the angiotensin-converting enzyme 2 (ACE2) receptor and therefore has a direct effect on the renin-angiotensin system (RAS). Apart from affecting numerous organs including lungs, heart, gastrointestinal system, spleen, brain and kidneys, the spike protein of SARS-CoV-2 could attack hematopoietic stem cells and hematopoietic progenitor cells in bone marrow (BM) microenvironment together with the precursor and mature blood cells. Within this hematopoietic viral spread context, it is crucial to search the clinicopathological correlations of COVID-19 in order to develop specific potential therapeutics against pleiotropic SARS-CoV-2 actions. Therefore, pharmacological disruption of the pathological cross-talk of local BM RAS and pulmonary RAS via administration of the tissue-RAS modulating agents such as soluble ACE2, angiotensin (1-7), TXA127 and MAS receptor agonists may prevent the clinical progression of the COVID-19 syndrome via reducing the hematopoietic virus propagation and systemic multi-organ spread.

Comparison of systemic inflammation activity and patients immune status in patients with various forms of atrial fibrillation and flutter

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): National Scientific Centre "M. D. Strazhesko Institute of Cardiology" Aims The inflammatory theory of atrial fibrillation and flutter arrhythmogenesis has attracted researcher`s attention in recent years, so the aim of our work is to compare the immune status of patients and systemic inflammation in paroxysmal and persistent atrial fibrillation and flutter in hypertensive people. Materials and methods The study involved 103 patients with hypertension and arrhythmias, who were divided into three main groups: group 1 (n = 35) - with paroxysmal atrial fibrillation (AF), group 2 (n = 38) - with persistent form of AF, group 3 (n = 30) - with persistent form of atrial flutter (AFl). For comparison, 2 control groups were formed: 4 (n = 23) - patients with hypertension, but without a history of arrhythmias and 5 (n = 21) - almost healthy people. The immune status of these patients was assessed by determining the level of monocytes (Mc), lymphocytes subpopulations and T-regulatory cells (T-reg) in the peripheral blood using flow cytometry. The activity of systemic inflammation was determined by serum highly specific C-reactive protein (CRP) level. Results It was noted that he number of classical CD14++CD16- and intermediate CD14++CD16+ Mc was significantly higher in patients with persistent AF and AFl comparing with patients without arrhythmias and healthy people (p&amp;lt;0.005). This fraction of Mc is able to produce proinflammatory cytokines and activate the local renin-angiotensin system, thus triggering the processes of fibrosis in the myocardium. Amount of non-classical CD14+CD16++ Mc was significantly lower in the second group both quantitatively and in percentage (p&amp;lt;0.005). The count of T cells with natural killer (TNK) activity was higher in all groups comparing to normal value, so statistical significance was observed only in comparison with the fifth group. The highest quantity of T-reg cells was found in healthy people comparing to other groups and a strong mathematical significance was obtained in all cases (p &amp;lt;0.005), both comparing the values in percentage and in μl. Patients with cardiac arrhythmias had signs of active systemic inflammation, such as high level of highly specific CRP. The highest one was in 2 group and exceeded the normal level by 6.7 times (8.31 ± 0.42) versus 1.25 ± 0.01) mg per l (p &amp;lt;0.001). Conclusions Patients with AF and AFl on the hypertension background comparing to hypertensive patients without arrhythmias or healthy people have a higher intensity of systemic inflammation because of higher levels of highly specific CRP, increased activity of proinflammatory subpopulation of monocytes, higher amount of T-cells with natural killer activity and reduced T-regulatory cells, whose main function is to control the immune response.

Distinct Responses in the Brain Compared to Lung in a Rat Model of Fat Embolism Syndrome

Fat embolism syndrome (FES) caused by release of emboli into the bloodstream after surgery or injury, can lead to severe neurological complications. We have previously shown that FES induced in rats by intravenous injection of triolein (T) causes pulmonary pathology after 48 hours that persists up to 10 weeks. Elevated expression of markers in the Renin Angiotensin System (RAS) are associated with pulmonary damage, and RAS inhibitors reduce pulmonary damage 1‐4. All components of the system (renin/ACE/AngII/AT1R) have been reported in the Central Nervous System and shown to be involved in neuroinflammation and eventual neurodegeneration5. To investigate the role of the brain RAS in response to FES, brains of T treated, and control rat models were examined for markers of RAS and neural pathology.Methodology24 rats received intravenous 200ul of T or Saline (S). Organs were processed at 48 hours or 10 weeks, sectioned, and immunostained with antibodies to Renin and Prorenin receptors in RAS; Glial Fibrillar Acidic Protein and Ib1a to identify makers of inflammation; Parp1 and Phospohistone S10 to identify cell death and proliferation respectively. Images were coded, blinded and quantified and statistically compared using GraphPad software.ResultsAs previously reported, lungs exhibited inflammation, vasculitis, and fibrosis at 48 hours and 10 weeks1,2. A significant increase in fat emboli was observed in the brain at 48 hours with persistence of micro‐emboli up to 10 weeks (S, N=6, relative emboli proportion (REP) = 7.2; FES N=5, REP = 11.0, p&lt;0.001). Contrary to the lung, vasculitis was not observed in the brain after 48 hours or 10 weeks (S, vs FES, 48 hours, p&lt;0.25; 10 weeks p&lt;0.35). Regional differences (hippocampus, cerebellum, cerebral cortex, hypothalamus) in expression of markers of RAS and markers of inflammation were observed in T versus S samples at 48 hours and 10 weeks.ConclusionThis study highlights differences in organ responses to FES and identifies distinct regions in the brain that may be susceptible to FES. Adaptations of components of brain RAS have been linked to increased oxidative stress through activation of NADPH oxidase and production of reactive oxygen species in the brain5. Release of reactive oxygen species and activation of inflammatory mediators is shown to be associated with progression of neurodegeneration and cognitive dysfunction5. Understanding the acute and long‐term impacts of FES on localized brain RAS, could provide further insight into the susceptibility and resistance of other organs RAS response.

Nicotine Treatment Resulted in Decreased Protein Expression of Prorenin and Soluble Prorenin Receptor in 3T3‐L1 cells

Over 36.5% of the United States population is affected by obesity, which is a major contributing factor to the rise of hypertension and cardiovascular disease. Furthermore, the CDC reports that over 16 million Americans suffer from nicotine‐related diseases. Nicotine consumption causes an increase in blood pressure and a decrease in adipogenesis. The prorenin receptor (PRR) and its soluble form (sPRR) are newly discovered components of a blood pressure regulatory pathway, the renin angiotensin system (RAS), and are upregulated during times of obesity. Currently, there is no research to understand the contrasting relationship between nicotine and PRR. Therefore, in this present study, we aimed to determine whether nicotine regulates blood pressure through an adipocyte PRR‐dependent.3T3‐L1 cells were grown to confluence and differentiated over 8 days. On day 8, cells were treated with nicotine dose response treatments: vehicle (water), 0.01 µM nicotine, 1 µM nicotine, or 10 µM nicotine. After 24‐hour treatment, cells were collected to measure protein levels of PRR and it soluble form, sPRR. Additionally, gene expression levels of PRR, renin, 18S, furin, and S1P were measured. Media from the cells was collected after 2 hours, 4 hours, and 24 hours of incubation to measure the secretion levels of sPRR into the media.Nicotine significantly decreased PRR protein expression at 1µM (n=2) compared to vehicle treatment (n=6) (vehicle: 1.00 0.37au; 1 µM: 0.46 0.09au; p &lt;0.05). Nicotine did not affect the gene expression of PRR but significantly decreased PRR and sPRR protein levels in a dose response manner compared to vehicle treatment (vehicle: 1.00 0.42au, n=6; 0.01 µM: 0.47 0.18au, n=4, 1uM: 0.32 0.12au, n=2; p &lt;0.05). Nicotine did not change the expression of S1P, and furin, two enzymes involved in PRR cleavage. Finally, renin and angiotensinogen (AGT) increased significantly in differentiated adipocytes treated with nicotine compared to those treated with vehicle. Together our data indicated that nicotine influences local renin angiotensin system by post‐transcriptionally down‐regulating PRR and sPRR protein and by upregulating renin and AGT. Together, these data suggest that nicotine could assert its effect on blood pressure and adipogenesis via an adipocyte‐PRR dependent mechanism.

The Effect of Hydroalcoholic Seed Extract of Securigera Securidaca on the Hepatic Renin-Angiotensin System in the Streptozotocin-Induced Diabetic Animal Model

Background: The aim of the study was to investigate the effect of hydroalcoholic seed extract of Securigera securidaca (S. securidaca) (HESS) on liver local reninangiotensin system (RAS) in streptozotocin-induced diabetic rats. Methods: Three groups of diabetic male Wistar rats were treated with different doses of HESS (100, 200, 400 mg/Kg-BW), and the results were compared with diabetic and healthy control groups. To test the effects of HESS on liver local RAS as well as its alternative pathway, the tissue levels of renin, angiotensin-converting enzyme (ACE), ACE2, angiotensin-II (Ang-II), and Ang-(1-7) were measured. The oxidative state of liver tissue was evaluated by biomarkers of malondialdehyde (MDA), total oxidant status (TOS), and total antioxidant status (TAS). Due to the association between local RAS activity and tissue inflammation, the production of interleukins (IL) IL-1, IL-6, tumor necrosis factor alfa (TNF-a), and IL-10 in the liver was assayed in the experimental group. Results: Dose-dependent effects of HESS showed that the highest dose of the extract had a reducing effect on the hepatic levels of local RAS components including angiotensinogen, ACE, and Ang-II. Surprisingly, despite the decrease in tissue level of ACE2, an increase in Ang-(1-7) tissue concentration was observed. Decreased local RAS activity through treatment with the highest dose of HESS was associated with decreased tissue levels of proinflammatory cytokines (IL-1, IL-6, TNF-a), and increased anti-inflammatory cytokine (IL-10). Most of the effects of the extract are attributed to its antioxidant properties. Conclusions: S. securidaca seed can be suggested as a suitable drug supplement to prevent hepatic complications of diabetes.

Salt-Sensitive Hypertension Induces Osteoclastogenesis and Bone Resorption via Upregulation of Angiotensin II Type 1 Receptor Expression in Osteoblasts.

Hypertension is a chronic-low grade inflammatory disease, which is known to be associated with increased bone loss. Excessive activity of the local renin–angiotensin system (RAS) in bone leads to increased bone resorption. As inflammatory cytokines may activate RAS components, we hypothesized that the elevated proinflammatory cytokine levels in hypertension activate bone RAS and thus lead to increased bone resorption. To investigate whether salt-sensitive hypertension (SSHTN) induces osteoclastogenesis and bone resorption, we generated a model of SSHTN in C57BL/6J mice by post-N ω-nitro-l-arginine methyl ester hydrochloride (l-NAME) high-salt challenge. SSHTN led to the reduction of distal femur trabecular number and bone volume fraction, while trabecular separation of femoral bone showed a significant increase, with no change in cortical thickness. Histomorphometric examination showed a significant reduction in trabecular bone volume fraction with an increased number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells and increased osteoclast surface fraction in the trabecular distal femur of hypertensive mice. Furthermore, analysis of gene expression in bone tissue revealed that TRAP and RANKL/OPG mRNA were highly expressed in hypertensive mice. TNF-α and angiotensin II type 1 receptor (AGTR1) mRNA and protein expression were also upregulated in SSHTN mice. These observations suggested that TNF-α may have an effect on AGTR1 expression leading to osteoclast activation. However, TNF-α stimulation did not promote AGTR1 mRNA expression in osteoclast precursors in culture, while TNF-α increased AGTR1 mRNA expression in osteoblast culture by activation of downstream p38. Angiotensin II was also shown to increase TNF-α-induced RANKL/OPG mRNA expression in primary osteoblast culture and osteoclastogenesis in a TNF-α-primed osteoblast and osteoclast precursor co-culture system. In addition, local injection of lipopolysaccharide into the supracalvariae of SSHTN mice markedly promoted osteoclast and bone resorption. In conclusion, mice with SSHTN show increased osteoclastogenesis and bone resorption due mainly to increased TNF-α and partly to the upregulation of AGTR1 in osteoblasts.

Альдостеронсинтаза, поліморфізм її гена CYP11B2 при артеріальній гіпертензії і асоційованих з нею кардіоваскулярних захворюваннях (огляд літератури)

В огляді надані дані зарубіжної та вітчизняної літератури щодо патогенетичної ролі альдостерону, рівнів альдостеронсинтази і поліморфізмів гена даного ферменту у хворих на різні форми артеріальної гіпертензії, при асоційованих з нею захворюваннях серця і судин, фібриляції передсердь, метаболічному синдромі, патології нирок, головного мозку. Розглядаються функції альдостерону, рівнів альдостеронсинтази і поліморфізмів гена даного ферменту в серцево-судинному ремоделюванні, можливості застосування даних маркерів для диференційно-діагностичних цілей, перспективи терапевтичного використання інгібіторів альдостеронсинтази серед різних категорій хворих з ознаками артеріальної гіпертензії.

Bone Marrow Origin of Coronary Artery Diseases: The Impact of the Local Renin-Angiotensin System.

The renin-angiotensin system (RAS) has both important systemic circulatory and local effects. The effects of local cardiac RAS on the cardiovascular system have been increasingly researched. In this study, we review the relationship between local bone marrow and local cardiac RAS and their impacts on atherosclerosis.

Can SARS-CoV-2 induce hematologic malignancies in predisposed individuals? A case series and review of the literature

IntroductionCoronavirus disease 2019 (COVID-19) may present with extrapulmonary manifestations, including hematologic changes. Previous studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) can interact with the renin-angiotensin system, ultimately causing increased production of angiotensin II. By reporting the cases of previously healthy young adults diagnosed with a hematologic malignancy after experiencing COVID-19, we raise the hypothesis that the SARS-Cov-2 infection could act as a trigger for leukemogenesis in predisposed individuals. MethodsThis was a case series performed through extraction of relevant clinical information from the medical records of three patients admitted to our Hematology unit between August 2020 and September 2020. Main ResultsConsidering the relatively rapid development of cytopenias following recovery from COVID-19, it cannot be ruled out that SARS-Cov-2 played a role in leukemogenesis in those patients. Based on previous in vitro studies, the renin-angiotensin system imbalance induced by SARS-CoV-2 could potentially promote in vivo leukemogenesis through several mechanisms. ConclusionDespite the advances in pathophysiological and clinical characterization of COVID-19, the consequences of the pandemic to the incidence of hematologic diseases are still to be elucidated. In this context, future dissection of the status of the local bone marrow renin-angiotensin system in leukemogenesis is a clinically relevant basic research area.